An Important Role of Osr1 in Outflow Tract Development
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Project SummaryCongenital heart defect (CHD) occurs in nearly 1 of 1000 live births, and approximately one third involvesmalformations of the cardiac outflow tract (OFT). Double outlet right ventricle (DORV) and overriding aorta (AO)are anomalies resulting from OFT misalignment. Currently the etiology of CHDs associated with OFT misalignmentis largely unknown and the cellular, genetic, molecular basis of OFT development has remained elusive. Osr1 encodesa zinc finger protein and is strongly expressed in the dorsal mesocardium during early heart development. We foundthat precursor cells expressing Osr1 contributed to the pulmonary trunk and deletion of Osr1 caused DORV or OA.The Osr1 null mouse embryos had OFT rotation problem and had abnormal patterning of the SHF precursor cells inthe dorsal mesocardium, which might result from proliferation defects in SHF. Interestingly, we and others reportedthat reduction of Pten, a well-established negative proliferation regulator, could rescue SHF proliferation defects,implying an inhibition role of Pten in modulating Osr1 regulated-SHF proliferation. We further identified potentialOsr1 direct targets: Cdk6 and CycD2 involving cell cycle regulators, and Hh-signaling modulator Smo. The lattersuggested an interaction between Osr1 and Hh-signaling, which is further supported by the finding that doublecompound heterozygous mutation of Osr1 and Smo caused a high penetration of DORV. Overall, these results stronglysuggested a genetic regulatory of Osr1, Hh-signaling and cell cycle genes in SHF for OFT development. Wehypothesize: Balanced by Pten inhibition, Osr1 modulates proliferation in SHF during OFT development bytranscriptional regulation of proliferation related genes and Hh-signaling. To test this hypothesis, we propose thefollowing three aims: (1) to determine how Osr1 modulates SHF cell proliferation for proper OFT alignment; (2) toinvestigate if and how Osr1 functions upstream of Hh-signaling in regulating OFT development; (3)Â to determine thatOsr1 regulation on SHF proliferation and DORV is balanced by Pten inhibition.Â This work will uncover new candidategenes and mechanisms underlying common forms of CHDs.